Abstract

Background:
The relative importance of malaria anaemia as a cause of childhood morbidity and mortality varies between and within regions. However, malaria anaemia remains an important cause of childhood morbidity and mortality. It has been estimated that globally, severe malaria anaemia occurs 1.42 to 5.66 million times per annum and kills an estimated 190,000 to 974,000 under-5 children. Studies from different countries endemic for malaria have emphasised the importance of anaemia in malaria-associated morbidity and mortality. Most of these studies have conclusively shown that severe malaria anaemia increases the risk of death in children with malaria; and in many reports, children with severe malaria anaemia often die before blood transfusion could be commenced. In addition, blood transfusion, which is the standard management for severe malaria anaemia, apart from not being available in many rural clinics, exposes the child to transfusion related infections such as human immunodeficiency virus (HIV). Better understanding of the pathogenesis of malaria anaemia therefore will enhance its prevention and management.
The pathogenesis of malaria anaemia is multifactorial and involves such mechanisms as immune and non-immune mediated haemolysis of parasitized and non-parasitized erythrocytes, bone marrow dysfunction, altered cytokine balance, nutritional deficits and interactions with common haemoglobinopathies and red cell defects such as glucose-6-phosphate dehydrogenase (G6PD) deficiency. An important component of the pathogenesis of malaria anaemia is iron delocalisation characterised by the sequestration of iron by the reticulo-endothelial tissues (the monocyte-macrophage system) as a result of malaria-induced inflammation. Iron sequestration creates a state of false iron deficiency which recovers after the inflammation has subsided. Therefore if the malaria-induced inflammation can be resolved more quickly, the degree and duration of malaria anaemia will be reduced. In addition, since the destruction of non-parasitized erythrocytes accounts for more than 90% of erythrocyte loss, use of anti-inflammatory drugs could minimize red cell loss.
Chloroquine is an antimalarial with proven anti-inflammatory properties. In addition, it is cheap, safe and has been shown to reduce iron delocalisation in vitro. A proof of concept study was designed to investigate its potential use in the management of children with mild malaria anaemia.
Aims and hypothesis:
The goal of the study was to investigate the effect of acute and continuing administration of chloroquine on haemopoietic response after a malaria episode. My hypothesis was that the anti-inflammatory and anti-macrophageal iron-loading effects of chloroquine will enhance erythropoietic recovery after a malaria episode.
Methodology:
The study was designed as a randomised placebo controlled trial and was conducted over two malaria seasons. In the first year, the study consisted of four arms with a 2x2 design and only two arms in the second year. In the first year, the participants were initially randomised to receive antimalarial treatment with either chloroquine-sulphadoxine-pyrimethamine or co-artemether. All children with negative peripheral smear for malaria parasite by day three were subsequently randomised to receive either weekly chloroquine or weekly placebo until day 90. In the second year of the study, all the children were initially treated with co-artemether; subsequently, those with negative peripheral smear for malaria parasites were randomised to weekly chloroquine or weekly placebo as in the first year. Children randomised to weekly chloroquine and weekly placebo were followed up for three months. Various clinical and laboratory measurements were conducted on days 0, 3, 7, 15, 30, 45, 70 and 90. In year two of the study, no data were collected on days seven and 70. The main outcome measure was change in haemoglobin from day three to day 30 and from day three to day 90. Other outcome measures were
1. Changes in Hb in the placebo arms of the CQ-SP and ACT treatment groups
2. Changes in measures of inflammation – neopterin and cytokines
3. Changes in markers of iron status
4. Prevalence of sub-microscopic parasitaemia
Results:
In 2007, 1445 children were placed under malaria surveillance, of which 105 malaria cases were recorded and 61 completed the 90 days follow-up. In 2008, of 1220 children under surveillance, 49 malaria cases were recorded, and 31 completed 90 days follow-up. There was no difference in Hb change from day three to day 30 and from day three to day 90 between the weekly chloroquine and weekly placebo arms. Although not statistically significant, the Hb change in children treated CQ-SP in 2007 was nearly twice the change in children treated with ACT at both days 30 and 90. The changes in the markers of iron status – MCV, MCH and ZnPP did not differ by treatment group and by randomisation group. During the acute malaria phase, neopterin concentration was high but by day 15, the levels had fallen to near zero levels and remained at this low level until day 30. Prevalence of sub-microscopic parasitaemia in the group was 15.1% and was similar in both randomisation arms. Iron deficiency was highly prevalent among the study participants. The independent predictors of Hb change were Hb at day 0, presence of iron deficiency, age of the child and height-for-age z score.
Conclusions:
Giving weekly chloroquine at a dose of 5mg/kg to children with mild anaemia associated with malaria did not confer any advantage to bone marrow recovery compared to children who received placebo. The data, however, suggests that the initial therapeutic dose of chloroquine (10mg/kg/day over three days) could have some positive effects on bone marrow recovery post malaria. The Hb recovery following treatment for malaria is determined by the age of the child, the Hb at diagnosis, the presence or absence of iron deficiency, and the height-for-age z score.